TOXI 142 |
| To effectively monitor protein phosphorylation events governing signaling cascades, we have developed a mass spectrometry-based methodology enabling the simultaneous quantification of tyrosine phosphorylation of specific residues on dozens of key proteins in a time-resolved manner. We have recently extended our analysis of the signaling networks to quantify the effects of kinase inhibitors targeting one or more proteins within the network. Interestingly, by quantifying protein phosphorylation it is possible to quantify drug efficacy and off-target effects in a variety of biological systems, including comparison of in vitro to in vivo effects. To assess off-target effects, multiple kinase inhibitors were compared to RNAi-based knockdown of the target protein. In each case, phenotypic quantification of drug efficacy was also quantified, through proliferation and apoptosis assays. Overall, combining mass spectrometry-based analysis of protein phosphorylation with phenotypic measurements and computational modeling should yield novel insights into the effects of kinase inhibitors on a network scale.
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Systems-wide Approaches to Understanding Drug Action and Toxicity
8:30 AM-12:00 PM, Thursday, August 23, 2007 BCEC -- 258C, Oral
Division of Chemical Toxicology |